The present invention relates generally to compounds containing a indolo[3,2-j]phenanthridine ring system. In particular, the present invention relates to compounds which are useful in the treatment of cancer and other diseases of humans and animals, particularly parasitic diseases, such as those of apicomplexan origin, compositions containing said compounds and methods of treatment using them.
Despite the significant advances made by the medical and scientific community over the last fifty years, a number of potentially mortal and debilitating mammalian, particularly humanp diseases are yet to be conquered by effective and adequate prophylaxis, treatment or cure. Two examples of such diseases are cancer and malaria.
Malaria is a disease which has been estimated to affect approximately 5% of the World""s population at any time, accounts for 25-50% of all hospital admissions in Africa, and is responsible for the death of between 1 to 2 million children each year.
The disease is caused by the entry of an apicomplexan parasite, Plasmodium, particularly P. falciparum or P. vivax into the bloodstream, through the bites of females of certain mosquito species which transmit the disease from one host to another. The parasite invades the liver and the red blood cells of the host and manifests its presence in the well recognised symptoms of chills, shivering, fever and profuse sweating. If left untreated, the disease chronically manifests itself through regularly recurring bouts of fever and prostration. Repeated attacks may result in the development of anaemia and enlargement of the liver and spleen. In the very young or old, the disease can be fatal.
Chloroquine has become the standard antimalarial for the treatment and prophylaxis of human malarial diseases and has become one of the most widely used drugs in the world. Increasingly, however, the parasites have developed resistance to the drug and P. falciparum is now almost untreatable with chloroquine and many strains of P. vivax are also resistant. Although quinine is often used against chloroquinine resistant strains of Plasmodium it is poorly tolerated and compliance is low. (White, N. J. (1992), J. Antimicrob. Chemother. 30, 571-85; Krishna, S. (1997), Br. Med. J., 315, 730-32). Other drugs such as mefloquine produce undesirable side effects.
Accordingly, there exists a need for new anti-malarial drugs which are effective against Plasmodium.
Another disease which has long been the subject of intense research by the medical and scientific communities is cancer. The growth, development and death of normal cells are highly regulated by mechanisms which are not yet fully understood. When these regulatory controls cease or malfunction, due to either external or genetic factors, the aberrant cells multiply at a greater rate than normal. Malignant tumours can metastasise throughout the body and invade other tissues and organs. The aetiology of cancer remains incompletely understood and despite advances in the detection and treatment of cancerous conditions over the last several decades, there remains a continued need for the development of new anticancer agents.
The present inventors have now isolated for the first time, specific compounds from extracts of certain Calothrix strains of cyanobacteria which have bioactivity against Plasmodium and cancer cells and may provide new treatments for mammalian diseases, including parasitic diseases such as malaria, or cancerous conditions. Without intending to limit the invention in any way, it has also been found that one mode of biochemical action of these compounds involves inhibition of DNA transcription or replication, and therefore, the present invention may also provide therapeutic and/or prophylactic methods for other conditions or infections.
Accordingly, in a first aspect, the present invention provides compounds of Formula (I): 
wherein
R is selected from hydrogen, alkyl, acyl, carboxyalkyl, carboalkoxyalkyl;
m and n are independently selected from 0, 1, 2;
each Y and each Z are independently selected from halo, acyl, nitro, amino, alkylamino, acylamino, hydroxy, acyloxy, alkoxy, alkyl, CO2H, CO2alkyl, CONX2 (where each X is independently H or alkyl), SO3H, SO2NX2 (wherein each X is independently H or alkyl), nitrile, formyl, carboxyalkyl, carboalkoxyalkyl;
a, b, c and d are independently selected from hydrogen, hydroxy, alkoxy, acyloxy, alkyl; or,
a and b together and/or c and d together independently form a carbonyl group (Cxe2x95x90O), an imine group (Cxe2x95x90Nxe2x80x94R1, where R1 is alkyl, hydroxy, alkoxy or amino NR2R3), or an alkene group (Cxe2x95x90CR2 R3, where R2 and R3 are independently hydrogen or alkyl);
or salt, derivative or prodrug thereof.
Compounds of Formula I can exist in their N-oxide form or as the free (unoxidized) base.
As used herein, the term xe2x80x9calkylxe2x80x9d denotes a straight, branched or cyclic fully saturated hydrocarbon residue of 1-6 carbon atoms including methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 3-methylpentyl, 2,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Particularly preferred alkyl are methyl, ethyl, n- and iso-propyl, n-, sec and t- butyl. Optionally the alkyl group may be substituted by one or more halo, hydroxy, phenyl, amino, alkoxy, acyl, nitro, carboxylic acid, or carboxylic ester groups, for example halomethyl groups (eg CF3, CBr3) hydroxy alkyl groups (eg hydroxymethyl, hydroxyethyl), benzyl, aminoalkyl and alkoxyalkyl.
The term xe2x80x9cacylxe2x80x9d is intended to refer to a group of the group of the formula xe2x80x94C(O)Rxe2x80x2, where Rxe2x80x2 is alkyl as defined above.
xe2x80x9cAcyloxyxe2x80x9d and xe2x80x9calkoxyxe2x80x9d are taken to refer to acyl and alkyl groups when linked by an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d denotes fluorine, chlorine, bromine or iodine.
Suitable alkoxy groups include methoxy, ethoxy, propoxy (n- and iso-) butoxy (n-, sec- and t-). Sitable carboxyalkyl groups include carboxymethyl, carboxyethyl, carboxybutyl, carboxypropyl. Suitable carboalkoxyalkyl include carbomethoxymethyl, carboethoxymethyl, carbopropoxymethyl, carbobutoxymethyl, carbomethoxyethyl, carboethoxyethyl, carbopropoxyethyl, carbobutoxyethyl, carbomethoxypropyl, carboethoxypropyl, carbopropoxypropyl, carbobutoxypropyl, carbomethoxybutyl, carboethoxybutyl, carbopropoxybutyl, carbobutoxybutyl. Suitable acyloxy include C(O)methyl, C(O)ethyl, C(O)propyl, C(O)butyl. Suitable CO2alkyl includes CO2methyl, CO2ethyl, CO2propyl, CO2butyl. Suitable amides include CONH2, CONHMe, CONHEt, CONHPr, CONMe2, CONEt2, CONPr2. Suitable amino groups include NH2, NHMe, NHEt, NHPr, NMe2, NEt2, NPr2.
The term xe2x80x9csalt, derivative or prodrugxe2x80x9d refers to any pharmaceutically acceptable salt, ester, solvate, hydrate or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein. However, it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts and prodrugs and derivatives can be carried out by methods known in the art.
Suitable pharmaceutically acceptable salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. Also, basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
The compounds of the invention may be in crystalline form either as the free compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
Any compound that is a prodrug of a compound of formula (I) is within the scope and spirit of the invention. The term xe2x80x9cpro-drugxe2x80x9d is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative.
It will be appreciated that some embodiments and derivatives of compounds of formula (I) may have an asymmetric centre, and therefore are capable of existing in more than one stereoisomeric form. The invention extends to each of these forms individually and to mixtures thereof, including racemates. The isomers may be separated conventionally by chromatographic methods or using a resolving agent.
In one embodiment, preferred compounds are where n and/or m are 0, 1 or 2, more preferably 0 or 1. In another embodiment, m and n are the same, ie both 0 or both 1 or both 2.
In another embodiment, preferred compounds are those where a and b together or c and d together form a carbonyl group. Particularly preferred embodiments are where a and b together and c and d together are both a carbonyl group.
Particularly preferred compounds are (IB) and its N-oxide (IA) 
It will be appreciated that compounds of Formula (I) may be obtained by the application of common synthetic manipulations to the naturally derived IA and IB.
It will also be recognised that the quinoline moiety and its N-oxide are readily interconvertible by standard chemical methods and that one may be produced from the other or mixtures of the two.
It will also be understood that where R is alkyl or acyl, this may be achieved by standard N-alkylation or N-acylation of the indolo-nitrogen, to give, for example,  greater than N-Me,  greater than N-ethyl or  greater than Nxe2x80x94C(O)CH3.
One or both of the quinonoid carbonyl groups may be subjected to reduction or nucleophilic addition manipulations such as those commonly employed in the art of organic synthetic chemistry. Thus, the reduction (for example with hydride reagents) of either of the carbonyl groups by one oxidation level affords  greater than CHxe2x80x94OH; or, where the quinone itself is reduced by one oxidation level, the hydroquinol of the pentacyclic ring structure. Either or both of the resulting OH group(s) may be further alkylated or acylated using art known alkylating and acylating methodology to produce, for example  greater than CHxe2x80x94OMe;  greater than CHxe2x80x94OEt;  greater than CHxe2x80x94OAc.
Further reduction of the aforementioned  greater than CHxe2x80x94OH group can afford the unsubstituted central ring where the carbonyl group is replaced by the  greater than CH2 group.
Each of the carbonyl groups may also be independently subjected to nucleophilic addition conditions with suitable nucleophiles to form imines, oximes or alkenes. Thus, nucleophilic addition of a primary amine, H2Nxe2x80x94R1(R=alkyl, preferably, methyl, ethyl or propyl), hydroxylamine, H2Nxe2x80x94OH, or a hydrazine H2NNR1R2 (R1 and R2 are independently hydrogen or alkyl, preferably, methyl, ethyl or propyl) affords the imine, oxime or hydrazine respectively. Wittig reaction of the carbonyl group with a suitable phosphorous ylide offers access to the corresponding substituted alkene eg Cxe2x95x90CH2. Treatment of either or both of the carbonyl groups under suitable conditions with a Grignard reagent e.g MeMg BR or EtMgBr, replaces the carbonyl group with  greater than C(OH)alkyl, eg  greater than C(OH)Me or  greater than C(OH)Et. Alcoholysis of either or both of the carbonyl groups under appropriate conditions, offers access to acetals ( greater than C(O alkyl)2) eg.  greater than C(O Me)2 or  greater than C(O Et)2.
In one form, one of a and b, or c and d may be carbonyl while the other is an imine, oxime or alkene. In another form, both or a and b, and c and d may be imine or oxime or alkene. In another form of the invention at least one of a and b, or c and d, or both of a and b, and c and d, is  greater than C(OH)alkyl or ( greater than C(O alkyl)2) where alkyl is preferably methyl, ethyl or propyl.
Where a, b, c and d are independently selected from hydrogen, hydroxy, alkoxy, acyloxy and alkyl, suitable aromatizing conditions may afford compounds where the central ring is aromatic and one of a or b and one of c or d have been eliminated. It will also be recognised that where hydroquinol is formed by suitable aromatizing conditions each aromatic OH group may be further alkylated or acylated. The quinol may also be formed by direct reduction of the quinone using known methods, for example catalytic reduction or by treatment with a hydride reagent, such as NaBH4, or treatment with SnCl2.
These fully aromatic compounds form another aspect of the invention.
Accordingly, in a second aspect, the invention also provides a compound of Formula II: 
wherein
Y, Z, R, m and n are as herein described and
R4 and R5 are independently selected from hydrogen, hydroxy, alkoxy, acyloxy or alkyl;
or a salt, derivative or prodrug thereof.
Compounds of Formula (II) can exist in their N-oxide form or as the free (unoxidized) base.
Preferred R4 and R5 include hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy, propoxy, acetoxy.
In one preferred embodiment of Formula (II) at least one of R4 or R5 is hydroxy. In another preferred form, both R4 and R5 are hydroxy. One or both of the hydroxy groups may be further alkylated or acylated. In still another embodiment, one of R4 or R5 are hydrogen. In still a further embodiment of the invention R4 and R5 are both hydrogen.
Also contemplated as being within the scope of the present invention are compounds where one or both of the terminal aromatic 6-membered rings is further substituted. By employing commonly known aromatic substitution methodology one or both of the unsubstituted 6-membered aromatic rings may be further substituted by halo (preferably chloro, bromo or iodo), acyl, sulfonate, alkyl or nitro groups. The nitro group may be reduced (for example, by treatment with SnCl2) to afford an aromatic amino group which may be further derivatized as described herein to afford alkylamino or acylamino groups. Alternatively, the aromatic nitro group may be converted into a hydroxy group, which may be further derivatised as described herein to afford alkoxy or acyloxy groups. Reduction of an aromatic acyl group under known conditions can provide an alkyl substituent. A sulfonic acid group (for example formed by treatment with fuming sulfuric acid) can be further converted ito sulfamides (SO2NX2). Alkyl groups can be oxidized to carboxylic acid groups (eg Me to CO2H) using conventional oxidation procedures known in the art. Substituents at the same oxidation level (eg carboxyic acids, carboxylic esters, amides, nitrites) may be interconverted using methods known in the art. Reduction of groups such as carboxylic acids and carboxylic esters (eg using hydride reagents) can afford aldehydes and hydroxy groups.
Methods for aromatic substitution and conversion of the resulting substiuents are known in the art and are described in March, Advanced Organic Chemistry (3rd. Edition), Wiley-Interscience and Larock, Conmprehensive Organic Transformations, 1989, VCH Publishers.
Preferred Y and Z include Cl, Br, I, OH, C(O)Me. C(O)Et, C(O)Pr, NH2, NHMe, NHEt, NHPr, NMe2, NEt2, NPr2, NHC(O)Me, OMe, OEt, OPr, CO2H, CO2Me, CO2Et, CO2Pr, CONH2, SO3H, SO2NH2, CHO, OC(O)Et, OC(O)CH3.
Electrophilic aromatic substitution by a Y group may occur at the 8-, or 9-, or 10- or 11-position. Electrophilic aromatic substitution by a Z group may occur at the 1-, or 2-, or 3- or 4-position.
Acylation and alkylation of indolo- and amino-N atoms and free hydroxy groups may be carried out using any conventional procedure such as those generally known in the art or described or referenced in the Third Edition of March (supra). Examples of acylating agents suitable for the process of acylating the compounds of formulae (I) and (II) are carboxylic acids, acid halides and acid anhydrides. The reaction may be carried out in a conventional manner, for example in a solvent such as pyridine, dimethylformamide, etc., optionally in the presence of a coupling agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide, and optionally in the presence of a catalytic base such as 4-dimethylaminopyridine. The product of the reaction may be isolated in a conventional manner. Examples of alkylating agents suitable for the process of alkylating the compound of formula (I) are alkyl halides, such as methyl, ethyl, propyl, and benzyl chlorides, bromides and iodides; and dialkyl sulfates like dimethyl and diethyl sulfate.
It will be understood that in order to perform some of the synthetic manipulations, it may be necessary to selectively protect and/or deprotect reactive groups such as keto, carboxyl, ester, amide, hydroxy or amino groups. Suitable protecting groups and protection/deprotection methods are described in Protective Groups in Organic Synthesis by T W Greene and P. Wutz, John Wiley and Son, (1991) the contents of which are incorporated herein by reference. It is also to be understood that where synthetic manipulations provide a reactive group such as CO2H, an ester, amide, an xe2x80x94OH or xe2x80x94NH2 group, these may be further derivatized by suitable protecting groups. Such protected derivatives are also considered to be within the scope of the invention.
In another aspect, the invention relates to methods for making compounds of Formula I and (II), salts, derivative and prodrugs thereof as well as protected derivatives of same.
Compounds IA and IB (also referred to herein as calothrixins A and B respectively) were isolated from Calothrix strains (Schlegel et al, J. Appl, Phycol. 10, 471-479 (1998)), extracts of which were screened for activity against HeLa cells and Plasmodium as described in the Examples. Compound IA was screened against a chloroquine-resistant strain (FAF6, derived from ITG2 strain) of the malaria parasite P. falciparum and was shown to inhibit growth (FIG. 1). The IC50 values of IA and chloroquine are presented in Table 1.
Accordingly, in another aspect, the present invention provides a method for the prophylaxis or treatment of malarial diseases in a mammal comprising administering to said mammal a prophylactic or treatment effective amount of a compound according to Formula (I) or (II), or a pharmaceutically acceptable salt, derivative or prodrug thereof.
The present invention also provides for the use of a compound according to Formula (I) or (II), or a pharmaceutically acceptable salt, derivative or prodrug thereof, in the manufacture of a medicament for the prophylaxis or treatment of malarial diseases, as well as agents therefor comprising said compound.
The compounds of Formula IA and IB were also examined for their efficacy in inhibiting the growth of cultured HeLa cells (FIG. 2). The IC50 values are depicted in Table 2.
Accordingly, in yet another aspect, the present invention provides a method for the treatment of cancer in a mammal, comprising administering to said mammal a treatment effective amount of a compound according to Formula (I) or (II) or a pharmaceutically acceptable salt, derivative or prodrug thereof.
The invention also provides for the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, derivative or prodrug thereof, in the manufacture of a medicament for the treatment of cancer, as well as agents therefor comprising said compound.
In yet another aspect, the invention provides a method for the inhibition of DNA transcription in mammal, comprising administering to said mammal an inhibition effective amount of a compound according to Formula (I) or (II), or a pharmaceutically acceptable salt, derivative or prodrug thereof.
The invention also provides for the use of a compound of Formula (I) or (II) in the manufacture of a medicament for the inhibition of DNA transcription in a mammal.
The invention further relates to a method for the treatment or prophylaxis of a disease or condition in a mammal, wherein inhibition of DNA transcription is effective, comprising administering to said mammal an inhibition effective amount of a compound according to Formula (I) or (II), or a pharmaceutically acceptable salt, derivative or prodrug thereof.
Still another aspect of the invention relates to the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, derivative or prodrug thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition wherein inhibition of DNA transcription is effective.
It will be recognised that where a and b, and c and/or are both hydroxy, these would be unstable compounds. Such compounds would not be suitable for use in the therapeutic methods of the invention.
The term xe2x80x9ccancerxe2x80x9d is used in its broadest sense and includes benign and malignant leukemias, sarcomas and carcinomas. The cancers contemplated by the present invention may be simple (monoclonal i.e. composed of a single neoplastic cell type), mixed (polyclonal, i.e. composed of more than one neoplastic cell type) or compound (i.e., composed of more than one neoplastic cell type and derived from more than one germ layer). Examples of simple cancers encompassed by the present invention include tumorous of mesenchymal origin (e.g. tumors of connective tissue, endothelial tissue, blood cells, muscle cells) and tumours of epithelial origin. Particular cancers contemplated by the present invention include, but are not limited to, fibrosarcoma, myxosarcoma, Ewing""s sarcoma, granulocytic leukemia, basal cell carcinoma, colon cancer, gastric cancer, breast cancer, cancer of the uterus, ovarian cancer, lung cancer, prostate cancer, throat cancer, and a variety of skin cancers.
As used herein, the term xe2x80x9cmammalxe2x80x9d refers, to but is not limited to: humans, primates, livestock animals (e.g. sheep, cows, horses, goats, pigs), laboratory test animals (e.g. mice, rats, guinea pigs, rabbits) companion animals (e.g. cats, dogs), or captive wild animals. Preferred mammals are humans.
The term xe2x80x9ctreatmentxe2x80x9d is intended to include the slowing, interruption, arrest, reduction in the number of cancerous cells or eradication or cure of the disease or condition.
The term xe2x80x9ceffective amountxe2x80x9d relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired prophylactic or therapeutic activity which desired activity may include the prevention, reduced severity, arresting or slowing the contraction or advancement of the condition. Dosing may occur as a single dosage or at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. The dosage is preferably in the range of 1 xcexcg to 1 g per kg of body weight per dosage. More preferably, the dosage is in the range of 1 mg to 1 g per kg of body weight per dosage. Suitably, the dosage is in the range of 1 xcexcg to 500 xcexcg per kg of body weight per dosage, such as 1 xcexcg to 200 mg per kg of body weight per dosage, or 1 xcexcg to 100 mg per kg of body weight per dosage. Other suitable dosages are in the range 1 mg to 250 mg per kg of body weight, including 1 mg to 10, 20, 50 or 100 mg per kg of body weight per dosage or 10 xcexcg to 100 mg per kg of body weight per dosage.
The active ingredient may be administered in a single dose or a series of doses. When a compound of the invention is administered to a mammal, the dosage rate can normally be determined by the attending physician or veterinarian with the dosage generally varying according to the age, weight, and response of the patient as well as the severity of the subject""s symptoms. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition.
Thus, in yet a further aspect, the invention also relates to compositions comprising a compound of Formula (I) or II or a salt derivative or prodrug thereof together with a pharmaceutically acceptable carrier, diluent or excipient.
The carrier must be pharmaceutically xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parental (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent), preservative, disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose, as herein above described, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the active ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question; for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
Where the mammal is non-human, the compounds according to the invention may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions include those adapted for:
(a) oral administration, external application, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
(b) parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension;
(c) topical application, e.g. as a cream, ointment or spray applied to the skin; or
(d) intravaginally, e.g. as a pessary, cream or foam.
In certain embodiments the present invention may also provide for compounds, agents, use, methods, or compositions which provide an advantage over (or avoid a disadvantage associated with) known compounds used in the chemotherapeutic prophylaxis or treatment of mammalian diseases such as malarial or cancerous conditions. Such advantages may include one or more of: increased therapeutic activity, reduced side effects, reduced cytoxicity to non-cancerous cells, improved physical characteristics for formulation into pharmaceutical compositions, greater patient compliance, improved stability or a more readily available means for obtaining said compound, e.g. simpler or higher yielding processes.
The compounds of the invention may also be useful in the treatment of other parasitic diseases such as those caused by worms, and spread by mosquitoes (eg African River virus).
Throughout this specification and the claims which follow, unless the context requires otherwise, the word xe2x80x9ccomprisexe2x80x9d and variations such as xe2x80x9ccomprisesxe2x80x9d and xe2x80x9ccomprisingxe2x80x9d will be understood to imply the inclusion of a stated integer or step or group of integers but not the exclusion of any other integer or step or group of integers.
Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
The invention will now be illustrated by the following non-limiting Examples and Drawings. These are provided to assist in the further understanding of the invention, and the particular materials, conditions and compounds described are not to be construed as limiting the scope thereof.